Influenza infection (also referred to as “influenza” or “the flu”) is one of the most common diseases known to man causing between three and five million cases of severe illness and between 250,000 and 500,000 deaths every year around the world. Influenza rapidly spreads in seasonal epidemics affecting 5-15% of the population and the burden on health care costs and lost productivity are extensive (World Healthcare Organization (WHO)).
There are three types of influenza virus (types A, B and C) responsible for infectious pathologies in humans and animals. The type A and type B viruses are the agents responsible for the influenza seasonal epidemics and pandemics observed in humans.
Influenza A viruses can be classified into influenza virus subtypes based on variations in antigenic regions of two genes that encode the surface glycoproteins hemagglutinin (HA) and neuraminidase (NA), which are required for viral attachment and cellular release. Currently, sixteen subtypes of HA (H1-H16) and nine NA (N1-N9) antigenic variants are known in influenza A virus. Influenza virus subtypes can further be classified by reference to their phylogenetic group. Phylogenetic analysis (Fouchier et al., 2005) has demonstrated a subdivision of HAs comprising two main groups (Air, 1981): inter alia the H1, H2, H5 and H9 subtypes in phylogenetic group 1 (herein also referred to as “group 1”) and inter alia the H3, H4 and H7 subtypes in phylogenetic group 2 (or “group 2”). Only some of the influenza A subtypes (i.e., H1N1, H1N2 and H3N2) circulate among people, but all combinations of the 16 HA and 9 NA subtypes have been identified in animals, in particular, in avian species. Animals infected with influenza A often act as a reservoir for the influenza viruses and certain subtypes have been shown to cross the species barrier to humans, such as the highly pathogenic influenza A strain H5N1.
The influenza type B virus strains are strictly human. The antigenic variations in HA within the influenza type B virus strains are weaker than those observed within the type A strains. Two genetically and antigenically distinct lineages of influenza B virus are circulating in humans, as represented by the B/Yamagata/16/88 (also referred to as “B/Yamagata”) and B/Victoria/2/87 (“B/Victoria”) lineages (Ferguson et al., 2003). Although the spectrum of disease caused by influenza B viruses is generally milder than that caused by influenza A viruses, severe illness requiring hospitalization is still frequently observed with influenza B infection.
Current approaches to dealing with annual influenza epidemics include annual vaccination, preferably generating heterotypic cross-protection. However, circulating influenza viruses in humans are subject to permanent antigenic changes that require annual adaptation of the influenza vaccine formulation to ensure the closest possible match between the influenza vaccine strains and the circulating influenza strains. Although yearly vaccination with influenza vaccines is the best way to prevent influenza, antiviral drugs, such as oseltamivir (TAMIFLU®) can be effective for prevention and treatment of influenza infection. The number of influenza virus strains showing resistance against antiviral drugs, such as oseltamivir is, however, increasing.
An alternative approach is the development of antibody-based prophylactic or therapeutic treatments to neutralize various seasonal and pandemic influenza viruses. The primary target of most neutralizing antibodies that protect against influenza virus infection is the globular head (HA1 part) of the viral HA protein that contains the receptor binding site, but that is subject to continuing genetic evolution with amino acid substitutions in antibody-binding sites (antigenic drift).
Recently, broadly cross-neutralizing antibodies recognizing an epitope in the conserved stem region of hemagglutinin of influenza A viruses of phylogenetic group 1 (including, e.g., the H1 and H5 influenza subtypes) have been identified (see, e.g., WO2008/028946), as well as cross-neutralizing antibodies recognizing a highly conserved epitope in the stem region of HA of influenza A viruses of phylogenetic group 2 (including, e.g., H3 and H7 subtypes) (WO 2010/130636). The neutralizing activity of these antibodies is restricted to either group 1 or group 2 influenza viruses. In addition, these antibodies are not capable of binding to and neutralizing influenza B viruses.
Furthermore, WO 2010/010466 discloses a human antibody FI6 binding to hemagglutinin and capable of binding to and neutralizing influenza A subtypes of group 1 (including H1 and H5 subtypes) and group 2 (including H3 and H7 subtypes). This antibody also does not bind HA from influenza B viruses.
In addition, US 2009/0092620 discloses a murine antibody recognizing an antigenic structure present in hemagglutinin of both the H1 and the H3 subtype and on hemagglutinin of influenza B viruses belonging to the B/Victoria and B/Yamagata groups. The antibodies inhibit the hemagglutination activity of several H3N2 strains implicating that this antibody binds an epitope in the globular head of HA.
In view of the severity of the respiratory illness caused by influenza A and influenza B viruses, as well has the high economic impact of the seasonal epidemics and the continuing risk for pandemics, there is an ongoing need for effective means for the prevention and treatment of influenza A and B subtypes. There is thus a need for binding molecules, preferably broadly neutralizing human binding molecules, capable of cross-neutralizing influenza A viruses of both phylogenetic group 1 and phylogenetic group 2, and preferably also influenza B viruses.